Carbapenems having an internally or externally alkylated mono- or bicyclic 2-quaternary heteroarylalxyl heteromethyl substituent

ABSTRACT

Carbapenems having the formula: ##STR1## wherein: R 1  is H; 
     R 4  and R 5  are independently H, CH 3  --, CH 3  CH 2  --, (CH 3 ) 2  CH--, HOCH 2  --, CH 3  CH(OH)--, (CH 3 ) 2  C(OH)--, FCH 2 , F 2  CH--, F 3  C--, CH 3  CH(F)--, CH 3  CF 2  --, (CH 3 ) 2  C(F)--; X is --S--, --SO--, --SO 2  --, --O-- or --NH; L is a bridging group comprising substituted or unsubstituted C 1  --C 4  straight, C 2  -C 6  branched or C 3  -C 7  cycloalkyl groups wherein the substituents are selected from C 1  -C 6  alkyl, O--C 1  -C 6  alkyl, S--C 1  -C 6  alkyl, CF 3 , N(C 1  -C 6  alkyl) 2  ; Y is a carboxy-containing substituent; Het is internally alkylated heteroarylium, ##STR2##  or externally alkylated heteroarylium, ##STR3##  their preparation and antibiotic use are disclosed.

BACKGROUND OF THE INVENTION

The present invention is concerned with carbapenem antibiotics having anexternal or internal quaternary mono- or bicyclicheteroarylalkylthiomethyl group in the 2-position.

Thienamycin is a known carbapenem, broad spectrum antibiotic of theformula: ##STR4## Other derivatives of A are also known.

The present externally or internally alkylated mono- or bicycli2-quaternary heteroarylalkylthiomethyl substituted carbapenems arebelieved to have an antibiotic spectrum comparable to A.

BRIEF DESCRIPTION OF DISCLOSES IN THE ART

Sankyo U.S. Pat. No. 4,377,591 and Japanese patent publications56-199682 and 56-60852 Shionogi Japanese patent publications 57-145086and 57-145087; and Roche U.K. patent publication No. 2 092 147A, alldescribe azabicycloheptene antibiotics having a 2-position substituentjoined through a thioalkylene bridge. U.S. Pat. No. 4,189,493 toBristol-Myers discloses externally alkylated heteroaryliumalkylthioazabicycloheptene antibiotics. U.S. Pat. No. 4,465,672, U.S.Pat. No. 4,260,627 and U.S. Pat. No. 4,267,188, all assigned to Merck &Co., Inc., disclose 2,6-substituted-1-carba-2-penem-3-carboxylic acidswherein the 2-substituent can be substituted or unsubstituted alkyl oraryl. However, none of the above references specifically describe thecarbapenem compounds of the present invention.

SUMMARY OF THE INVENTION

Carbapenems having the formula: ##STR5## wherein

R¹ is H:

R⁴ and R⁵ are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂--, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂, F₂ CH--, F₃ C--, CH₃ CH(F)--,CH₃ CF₂ --, (CH₃)₂ C(F)--; X is --S--, --SO--, --SO₂ --, --O-- or --NH;L is a bridging group comprising substituted or unsubstituted C₁ -C₄straight, C₃ -C₆ branched or C₃ -C₇ cycloalkyl groups wherein thesubstituents are selected from C₁ -C₆ alkyl, O--C₁ -C₆ alkyl, S--C₁ -C₆alkyl, CF₃, N(C₁ -C₆ alkyl)₂ ; Y is a carboxy-containing substituent;Het is internally alkylated heteroarylium, ##STR6## or externallyalkylated heteroarylium, ##STR7## their preparation and antibiotic useare disclosed.

DETAILED DESCRIPTION OF THE INVENTION

The invention is embodied in a compound having the formula: ##STR8##wherein:

R¹ is hydrogen;

R⁴ and R⁵ are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂--, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂, F₂ CH--, F₃ C--, CH₃ CH(F)--,CH₃ CF₂ --, (CH₃)₂ C(F)--; X is --S--, --SO--, --SO₂ --, --O-- or --NH;

L is a bridging group comprising substituted or unsubstituted C₁ -C₄straight, C₂ -C₆ branched or C₃ -C₇ cycloalkyl groups wherein thesubstituents are selected from C₁ -C₆ alkyl, O--C₁ -C₆ alkyl, S--C₁ -C₆alkyl; CF₃, N(C₁ -C₆ alkyl)₂ ;

wherein Het is a mono- or bicyclic heteroarylium group containing from5-11 ring atoms of which up to 5 are heteroatoms, in addition to thequaternary nitrogen, being ##STR9## or ##STR10## wherein R² is (1) anunsubstituted or substituted C₁ -C₆ alkyl radical;

(2) an unsubstituted or substituted C₂ -C₆ alkenyl radical;

(3) an unsubstituted or substituted C₂ -C₆ alkynyl radical;

(4) a C₃ -C₇ cycloalkyl radical in which the ring is substituted orunsubstituted and one or more atoms may be replaced by a heteroatom;

(5) a C₃ -C₇ cycloalkyl methyl radical in which the ring may besubstituted and one or more atoms may be replaced by a heteroatom;

(6) an unsubstituted or substituted C₅ -C₇ cycloalkenyl radical;

(7) an unsubstituted or substituted bivalent C₂ -C₆ alkylidene radical,optionally interrupted by a heteroatom, and joined to the heteroaryliumgroup to form a ring which is carbocyclic or in which one or more atomsis replaced by a heteroatom and wherein the new ring may contain one ormore double bonds;

(8) an unsubstituted or substituted phenyl or heteroaryl radical;

(9) an unsubstituted or substituted phenyl (C₁ -C₄ alkyl) or heteroaryl(C₁ -C₄ alkyl) or radical;

(10) a cyano (C₁ -C₄ alkyl) radical;

(11) a carboxy (C₁ -C₄ alkyl) radical;

(12) a sulfo (C₁ -C₄ alkyl) radical;

(13) a carbamoyl (C₁ -C₄ alkyl) radical;

(14) a phosphonyl (C₁ -C₄ alkyl) radical;

(15) a hydroxy (C₁ -C₄ alkyl) radical; or

(16) an amino (C₁ -C₄ alkyl) radical in which the nitrogen atom isunsubstituted or substituted with one to three C₁ -C₄ alkyl groups;

wherein the substituents in the above definitions of R² areindependently selected from the group consisting of:

(a) a trifluoromethyl group;

(b) a halogen atom;

(c) an unsubstituted or substituted C₁ -C₄ alkoxy radical;

(d) a hydroxy group;

(e) an unsubstituted or substituted (C₁ -C₆ alkyl) carbonyloxy radical;

(f) a carbamoyloxy radical which is unsubstituted or substituted onnitrogen with one or two C₁ -C₄ alkyl groups;

(g) a C₁ -C₆ alkylthio radical, C₁ -C₆ alkylsulfinyl radical or C₁ -C₆alkylsulfonyl radical, each of which is unsubstituted or substituted onthe alkyl group;

(h) a sulfo group;

(i) a sulfamoyl group which is unsubstituted or substituted on nitrogenby one or two C₁ -C₄ alkyl groups;

(ia) an amino group;

(ib) a mono (C₁ -C₄ alkyl) amino or di(C₁ -C₄ alkyl) amino group, eachof which is unsubstituted or substituted on the alkyl group;

(j) a formylamino group;

(k) an unsubstituted or substituted (C₁ -C₆ alkyl)carbonylamino radical;

(l) a (C₁ -C₄ alkoxyl) carbonylamino radical;

(m) a ureido group in which the terminal nitrogen is unsubstituted orsubstituted with one or two C₁ -C₄ alkyl groups;

(n) an arylsulfonamido or a (C₁ -C₆ alkyl)sulfonamido group;

(o) a cyano group;

(p) a formyl or acetalized formyl radical;

(q) an unsubstituted or substituted (C₁ -C₆ alkyl)carbonyl radicalwherein the carbonyl is free or acetalized;

(r) an unsubstituted or substituted phenylcarbonyl or heteroarylcarbonylradical;

(ra) a hydroximinomrthyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group;

(s) a carboxyl group;

(t) a (C₁ -C₆ alkoxy)carbonyl radical;

(u) a carbamoyl radical which is unsubstituted or substituted onnitrogen by one or two C₁ -C₄ alkyl groups;

(v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in whichthe nitrogen atom may be additionally substituted by a C₁ -C₄ alkylgroup;

(w) a thiocarbamoyl group;

(x) a 5-(1H)-tetrazolyl group;

(xa) an amidino group ##STR11## (xb) a carboxamidino group ##STR12##where R', R" and R"' are as defined above; (xc) a guanidinyl group whereR" in (ab) above is NR^(iv) R^(v) and R^(iv) and R^(v) are as definedfor R' through R"' above;

(y) a phosphonate group --P(O) (O⁻)OR' where R' is C₁ -C₃ alkyl;

(z) an alkyl phosphonate group --(CH₂)_(n) P(O) (O⁻) (OR') where n=1 to3 and R' is C₁ -C₃ alkyl;

(aa) hydrogen;

(ab) an unsubstituted or substituted C₁ -C₆ alkyl radical;

(ac) an unsubstituted or substituted C₂ -C₆ alkenyl radical;

(ad) an unsubstituted or substituted C₂ -C₆ alkynyl radical;

(ae) a C₃ -C₇ cycloalkyl radical in which the ring is substituted orunsubstituted and one or more atoms may be replaced by a heteroatom;

(af) a C₃ -C₇ cycloalkyl methyl radical in which the ring may besubstituted and one or more atoms may be replaced by a heteroatom;

(ag) an unsubstituted or substituted C₅ -C₇ cycloalkenyl radical;

(ah) an unsubstituted or substituted phenyl or heteroaryl radical; and

(ai) an unsubstituted or substituted phenyl (C₁ -C₄ alkyl) or heteroaryl(C₁ -C₄ alkyl) radical; and

R³ is

(a) hydrogen;

(b) an unsubstitued or substituted C₁ -C₆ alkyl radical;

(c) an unsubstituted or substituted C₂ -C₆ alkenyl radical;

(d) an unsubstituted or substituted C₂ -C₆ alkynyl radical;

(e) a C₃ -C₇ cycloalkyl radical in which the ring is substituted orunsubstituted and one or more atoms may be replaced by a heteroatom;

(f) a C₃ -C₇ cycloalkyl methyl radical in which the ring may besubstituted and one or more atoms may be replaced by a heteroatom;

(g) an unsubstituted or substituted C₅ -C₇ cycloalkyl radical;

(h) an unsubstituted or substituted phenyl or heteroaryl radical;

(i) an unsubstituted or substituted phenyl (C₁ -C₄ alkyl) or heteroaryl(C₁ -C₄ alkyl) radical; and

(j) a trifluoromethyl group;

(k) a halogen atom;

(l) an unsubstituted or substituted C₁ -C₄ alkoxyl radical;

(m) a C₁ -C₆ alkylthio radical, C₁ -C₆ alkylsulfinyl radical or C₁ -C₆alkylsulfonyl radical, each of which is unsubstituted or substituted onthe alkyl group;

(n) a mono (C₁ -C₄ alkyl) amino or di(C₁ -C₄ alkyl)amino group, each ofwhich is unsubstituted or substituted on the alkyl group; or

(i) a cyano group; and

Y is

(i) COOH or a pharmaceutically acceptable ester or salt thereof,

(ii) COOR wherein R is a removable carboxy protecting group, such asp-nitrobenzyl, benzyl or allyl,

(iii) COOM wherein M is an alkali metal, or

(iv) COO⁻ ; provided that when Y is other than (iv) a counterion Z⁻ isprovided.

As used herein, the term ∓heteroatom" means nitrogen, oxygen, or sulfur,independently selected where more than one heteroatom is involved.

Representative L groups are substituted or unsubstituted branched orlinear C₁ -C₄ alkyl and include --CH₂ --, --CH(CH₃)--, --CH(C₂ H₅)--,--(CH₂)₂₋₄, --CH(CH₃)--CH₂ --, CH₂ --CH(OCH₃)--, --CH(CH₃)--(CH₂)₂ --,--CH(CH₂ OH)--CH₂ --, --CH(CF₃)--CH₂ --, and the like.

Preferred L groups are --CH₂ --, --CH(CH₃)--, --(CH₂)₂ --, and--CH(CH₃)CH₂ --.

Examples of useful R² groups are --CH₃, --(CH₂)₁₋₃ --CH₃, ##STR13##--(CH₂)₁₋₃ --O--CH₃, --CH₂ --CN, CH₂ --COOC₁ -C₃ alkyl, --(CH₂)₂ --N(C₁-C₃ alkyl)₂, --CH₂ --COOH(Na), --(CH₂)₂ --SO₃ H(Na), ##STR14## CH₂CONH₂, --(CH₂)₂ --N⁺ (CH₃)₃ and the like.

Preferred R² groups are the C₁ -C₆ alkyls, both substituted andunsubstituted, carboxy (C₁ -C₄ alkyl), carbamoyl (C₁ -C₄ alkyl), sulfo(C₁ -C₄ alkyl), heteroaryl (C₁ -C₄ alkyl) or cyano (C₁ -C₄ alkyl).

Preferred substituents are CN, CON(CH₃)₂, CONH₂, SOCH₃, SO₂ CH₃, CO₂ H,SO₃ H, SO₂ NH₂ and ##STR15##

Examples of useful R³ groups are hydrogen, N(C₁ -C₃ alkyl), OC₁ -C₄alkyl, C₁ -C₄ alkyl, CN, CF₃, CH₂ OH and the like.

Preferred R³ groups are H, --CH₃, --OCH₃, CN, --SO₂ CH₃, CH₂ CN, and thelike.

Preferred R⁴ and R⁵ groups are where R⁴ is hydrogen and R⁵ is ##STR16##

The ##STR17## moiety is mono- or bicyclic quaternary heteroarylium grouphaving 5-11 ring atoms of which, in addition to the quaternary N⁺, up tofour can be heteroatoms.

Representative ##STR18## groups are: ##STR19##

A preferred ##STR20## group is monocyclic heteroarylium having 5-6 ringatoms and optionally one heteroatom additional to the N atom alreadypresent, e.g., ##STR21## where R² and R³ are as defined in the preferredlist above and L is --CH₂ -- or --CH₂ CH₂ --.

An especially preferred subclass includes the nuclei shown above whereR³ (where present) is --CH₃, L is --CH₂ -- or --CH₂ CH₂ -- and R² is C₁-C₆ alkyl, unsubstituted or substituted by --CN, --CON(CH₃)₂, --CONH₂,--SOCH₃, --SO₂ CH₃, --CO₂ H, --CO₂ H, --SO₃ H, --SO₂ NH₂ and ##STR22##

Further preferred compounds of Formula I include those where R¹ is H orCH₃ and ##STR23## is ##STR24##

The compounds of Formula I include inner (Zwitterion) salts when Y isCOO⁻ e.g. ##STR25## or, when Y is other than COO⁻, salts with anexternal, physiologically acceptable counterion Z⁻ such as Cl⁻, Br⁻, I⁻,OCH₃ ⁻, OSO₂ CF₃ ⁻, OP(O) (O phenyl)₂ ⁻ and the like.

The inner salts are preferred.

Again, the compounds of Formula I include the stereoisomers as mixturesand as separate isomers.

A preferred isomer configuration is: ##STR26##

Representative useful internally alkylated monocyclic ##STR27## groupsare substituted and unsubstituted pyridinium, pyridazinium,pyrimidinium, pyrazinium, pyrazolium, triazolium, imidiazolium,thiazolium, oxazolium and the like.

Preferred Formula I compounds internally alkylated are those wheremonocyclic ##STR28## is a six membered heterocycle, such as substitutedor unsubstituted pyridinium, pyridazinium or pyrazinium, and preferablysubstituted or unsubstituted pyridinium, wherein the substituents (oneor more) are selected from OH, NH₂, NHCH₃, OCH₃, COO--C₁ -C₃ alkyl,C(O)NHOH, phenyl, N(CH₃)₂, C(O)CH₃, C(O)N(CH₃)OH, SO₃ H, SCH₃, CHO,COOH, S(O)CH₃, SO₂ CH₃, SO₂ NH₂, SO₂ NHCH₃, SO₂ CH₃, CN, C₅ NH₂, CONH₂,CONH(CH₃), CH═N--OH, C₁ -C₆ alkenyl and substituted and unsubstituted C₁-C₆ alkyl.

The preferred substituents are unsubstituted C₁ -C₆ alkyl, C₁ -C₆alkenyl, and substituted C₁ -C₆ alkyl wherein the substituents (one ormore) are selected from OH, NH₂, NHCH₃, OCH₃, --COO--C₁ -C₃ alkyl,C(O)NHOH, ##STR29## N(CH₃)₂, C(O)CH₃, C(O)--N(CH₃)OH, SO₃ H, SCH₃, CHO,COOH, S(O)CH₃, SO₂ CH₃, SO₂ NH₂, SO₂ NHCH₃, CN, CSNH₂, CH═N--OH, CONH₂,CONH(CH₃).

Representative examples of preferred ##STR30## pyridinium groups arethose having the formulae ##STR31##

Representative examples of preferred monocyclic ##STR32## other thenpyridinium are those having the following formulae: ##STR33##

In another preferred embodiment, the --N⁺ group is a quaternized,bicyclic, substituted or unsubstituted heteroaryl, containing inaddition to the quaternary N, up to 4 additional heteroatomsindependently selected from O, N and S, and 9-10 total ring atoms.

Representative useful ##STR34## groups are substituted and unsubstitutedquinolinium, isoquinolinium, quinoxalinium, isocinolinium,thienopyridinium, furopyridinium, naphthyridinium, pyrazinopyridinium,##STR35## where D is a C₂₋₆ alkylene ring which may be interrupted byone or more O, S or N heteroatoms.

Preferred Formula I compounds are those where ##STR36## is a bicyclic 9or 10 membered ring, and more preferably substituted or unsubstitutedquinolinium, isoquinolinium, or thienopyridinium.

The preferred substituents on the bicyclic heteroaryl groups are OH, C₁-C₃ alkyl, NH₂, CH═NOCH₃, CF₃, halo, preferably Br or Cl, O--C₁ -C₃alkyl, COOH, CHO, SO₃ H, CONH₂, SO₂ NH₂, N(C₁ -C₃ alkyl)₂, CH₂ CO₂ H,CH₂ OH, ##STR37## CH₂ SO₃ H, CN, CONH₂, CH₂ CN, CH₂ CONH₂, CH₂ N(C₁ -C₃alkyl)₂ and the like.

Representative examples of useful bicyclic ##STR38## groups are:##STR39##

Where ##STR40## representative examples of preferred groups are:##STR41## wherein R¹ is H or a suitable substituent such as C₁ -C₃alkyl, CN, CO₂ H, SO₃ H, ##STR42## CONH₂, NH₂, NH(C₁ -C₃ alkyl), N(C₁-C₃ alkyl)₂, OH, O(C₁ -C₄ alkyl), SO₂ NH₂, CH₂ OH, CH₂ N(C₁ -C₃ alkyl)₂,CH₂ CO₂ H, CH₂ CN, CH₂ CONH₂, halo, CH₂ ##STR43## and R² substituted orunsubstituted C₁ -C₄ alkyl wherein the substituents are selected fromOH, N(C₁ -C₃ alkyl)₂, CO₂ H, SO₃ H, CN, CONH₂, and O(C₁ -C₄ alkyl).

Especially preferred ##STR44## groups are the unsubstituted groupsespecially where (a) A is (CH₂)₂ or (CH₂)₃, and B is a single bond, (b)A is CH₂ and B is CH₂ or (CH₂)₂, or c) A is a single bond and B is(CH₂)₂₋₃, and the heteroaryl moiety is preferably pyridinium,thiazolium, or imidazolium.

The compounds of Formula I include inner (Zwitterion) salts when Y isCOO⁻ e.g. ##STR45## or, when Y is other than COO⁻, salts with anexternal, physiologically acceptable counterion Z.sup.(-) e.g. ##STR46##R°^(a) is a pharmaceutically acceptable ester, e.g., pivaloyloxymethyl,phthalidyl, phthalimidomethyl, acetoxymethyl, ethoxycarbonyloxyethyl,pivaloyloxyethyl, 4-methyl-2-oxo-1,3-dioxolen-5-yl-methyl or salt group;and Z⁻ is Cl⁻, Br⁻, I⁻, OH⁻, HCO₃ ⁻, CH₃ CO₂ ⁻ and the like. The innersalts are preferred.

Again, the compounds of Formula I include the stereoisomers as mixturesand as separate isomers.

Compounds having the (5R,6S,8R) stereochemistry shown below arepreferred ##STR47##

Where ##STR48## or when L contains a chiral center, the side chainchirality leads to diastereomeric products. The products can beseparated by conventional methods, used as mixtures or synthesizedstereospecifically from optically active mercaptans.

The compounds of the present invention (I) are valuable antibioticsactive against various Gram-positive and Gram-negative bacteria andaccordingly find utility in human and veterinary medicine.Representative pathogens which are sensitive to antibiotics I include:Staphylococcus aureus, Escherichia coli, Klebsiella Pneumoniae, Bacillussubtilis, Salmonella typhosa, Pseudomonas and Bacterium proteus. Theantibacterials of the invention are not limited to utility asmedicaments; they may be used in all manner of industry, for example:additives to animal feed, preservation of food, disinfectants, and inother industrial systems where control of bacterial growth is desired.For example, they may be employed in aqueous compositions inconcentrations ranging from 0.1 to 100 parts of antibiotic per millionparts of solution in order to destroy or inhibit the growth of harmfulbacteria on medical and dental equipment and as bactericides inindustrial applications, for example in waterbased paints and in thewhite water of paper mills to inhibit the growth of harmful bacteria.

The compounds of this invention may be used in any of a variety ofpharmaceutical preparations. They may be employed in capsule, powderform, in liquid solution, or in suspension. They may be administered bya variety of means; those of principal interest include: topically orparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents.Alternatively, the active ingredient may be in powder form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile water. Topical applications may be formulated in hydrophobicor hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration--the parenteral route by injection beingpreferred for generalized infections. Such matters, however, are left tothe routine discretion of the therapist according to principles oftreatment well known in the antibiotic art. In general, a daily dosageconsists of from about 5 to about 600 mg of active ingredient per kg ofbody weight of the subject in one or more treatments per day. Apreferred daily dosage for adult humans lies in the range of from about10 to 240 mg of active ingredient per kg of body weight. Another factorinfluencing the precise dosage regimen, apart from the nature of theinfection and peculiar identity of the individual being treated, is themolecular weight of the chosen species of this invention (I).

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from 0.1% to 99% of active material, the preferredrange being from about 10-60%. The composition will generally containfrom about 15 mg to about 1500 mg of the active ingredient; however, ingeneral, it is preferable to employ a dosage amount in the range of fromabout 250 mg to 1000 mg. In parenteral administration, the unit dosageis usually the pure compound I in sterile water solution or in the formof a soluble powder intended for solution.

The preferred method of administration of the formula I antibiotic isparenteral by i.v. infusion, i.v. bolus, or i.m. injection.

For adults, 5-50 mg of Formula I antibiotic per kg of body weight given2, 3, or 4 times per day is preferred. Preferred dosage is 250 mg to1000 mg of the Formula I antibiotic given two (b.i.d.) three (t.i.d.) orfour (q.i.d.) times per day. More specifically, for mild infections, andparticularly urinary tract infections, a dose of 250 mg t.i.d. or q.i.d.is recommended. For moderate infections against highly susceptible grampositive and gram negative organisms, a dose of 500 mg t.i.d. or q.i.d.is recommended. For severe, life-threatening infections againstorganisms at the upper limits of sensitivity to the antibiotic, a doseof 1000 t.i.d. or q.i.d. is recommended.

For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 timesper day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usuallyrecommended.

Antibiotic compounds of Formula I are of the broad class known ascarbapenems or 1-carbadethiapenems. Certain of these carbapenems aresusceptible to attack by a renal enzyme known as dehydropeptidase (DHP).This attack or degradation may reduce the efficacy of the carbapenemantibiotic. Inhibitors of DHP and their use with carbapenem antibioticsare disclosed in the prior art [see published European PatentApplication No. 79102616.4 filed July 24, 1979 (Pat. No. 10573);79102615.6, filed July 24, 1979 (Application No. 15573); and No.82107174.3, filed Aug. 9, 1980 (Application No. 72014)].

The present I compounds may, where DHP inhibition is desired ornecessary, be combined or used with the appropriate DHP inhibitor asdescribed in the aforesaid published applications. Thus, to the extentthat the cited European patent applications (1.) define the procedurefor determining DHP susceptibility of the present carbapenems and (2.)disclose suitable inhibitors, combination compositions and methods oftreatment, they are incorporated herein by reference. A preferred weightratio of I compound:DHP inhibitor in the combination compositions isabout 1:1. A preferred DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

These combination compositions and their use is another embodiment ofthe present invention.

The compounds of Formula I may be prepared by any convenient process.

PREPARATION OF COMPOUNDS OF FORMULA I

Due to the varied nature of Het, several different synthetic approachesare used to prepare compounds of type I. These are summarized below.Implicit in these synthetic routes is the fact that when Het contains afunctional group which might interfere with the intended course of thereaction, the offending group is blocked. For example, when a basicnitrogen group is present as --NHR or --NH₂, it is usually protected byacylation (--CO₂ -allyl or --CO₂ PNB) or silylation. In the case of acarboxyl group, protection is achieved via use of a suitable ester, suchas allyl or PNB.

In many instances, the actual order of carrying out the individualsynthetic transformations in a synthetic scheme can be permuted forreasons of synthetic expediency. Thus, many of the examples listed belowcould proceed with equal facility by having the order of operationschanged.

SYNTHETIC METHODOLOGY A. Key Intermediate II ##STR49## X and Het are asdefined above;

R⁷ is a suitable ester protecting group such as p-nitrobenzyl, allyl, orthe like;

R⁸ is a suitable alcohol protecting group such as (CH₃)₃ Si--, t-BuMe₂Si, p-nitrobenzyloxycarbonyl, allyloxycarbonyl, or the like.

Method IIa ##STR50##

Y= ##STR51## or the like;

R⁷, and R⁸ are as defined above;

M=Li, MgX, Cu or the like.

Method IIb ##STR52##

Y and M are as defined above;

R⁸ =triorganosilyl, allyloxycarbonyl, or the like;

R⁷ =allyl, benzyl or the like;

Q=--Cl, --Br, --SR, --SO₂ R or the like;

R⁹ =H, CH₃ ;

strong base=LiNiPr₂, LiN(TMS)₂, ##STR53## etc.

Method IId ##STR54##

X, M, and Y are as defined above;

R⁷ =allyl, benzyl or the like;

R⁸ =triorganosilyl, allyloxycarbonyl, or the like; strong base is asdefined previously;

R⁹ =H, CH₃ ;

Z=OSO₂ CH₃, ##STR55## --Cl, Br, I or the like;

activating agent=O₂, MoOPH, Br₂, I₂, BrSO₂ Ar etc.

The --OH product of reaction with O₂ or MoOPH can be further activatedwith ClSO₂ CH₃, ##STR56##

Method IIe ##STR57##

Z, R⁵, M and Y are as defined previously;

R⁷ =allyl, benzyl or the like;

R⁸ =triorganosilyl, allyloxycarbonyl or the like;

R¹⁰ =--Cφ₃, -tetrahydropyranyl or the like;

R⁹ =H, CH₃ ;

in addition, Z can be an activated olefin or alkyne ##STR58##

W=electron withdrawing group such as --CO₂ R, ##STR59## --CN, --SO₂ R,etc.

Variations of the above methodologies involving permutation of steps isalso possible. For example, the phosphorane group on nitrogen can beintroduced at a later stage by "standard" procedures (see below).##STR60##

One example of such a route is shown in Method IIf.

Method IIf ##STR61##

Method IIg ##STR62##

Y, R⁸, R⁹ are as previously defined;

R"=t-Bu, R₃ Si such as Me₃ Si, t-BuMe₂ Si;

L= ##STR63## --OR such as OEt, OMe, OiPr, etc.

Method IIh ##STR64##

all substituents as previously defined

Method IIi ##STR65##

Completion of the Synthesis from Intermediate II--Methods a-i ##STR66##

In those cases where the final product will contain a quaternizedheterocyclic group, an additional alkylation step would be added.

Method j ##STR67##

EXAMPLE 3

Utilizing the procedures of Examples 1-2, the following externallyalkylated compounds listed in Table I are prepared, wherein R¹ for eachcompound is hydrogen. Remarks relative to the procedures are presentedin the footnotes to Table I.

                  TABLE I                                                         ______________________________________                                         ##STR68##                                                                     poundCom-                                                                           L                                                                                        ##STR69##      R.sup.2                                      ______________________________________                                         1.   CH.sub.2                                                                                  ##STR70##     CH.sub.3                                       2.   CH         "              "                                                   CH.sub.3                                                                 3.   CH.sub.2 CH.sub.2                                                                        "              "                                              4.   CH.sub.2 CH.sub.2 CH.sub.2                                                               "              "                                              5.   CH.sub.2 CH.sub.2                                                                        "              CH.sub.2 CH.sub.3                              6.   "          "              CH.sub.2 CO.sub.2 H                            7.   "          "              CH.sub.2 CONH.sub.2                            8.   "          "                                                                                             ##STR71##                                     9.   "          "              CH.sub.2 SOCH.sub.3                           10.   "                                                                                         ##STR72##     CH.sub.3                                      11.   CH.sub.2 CH.sub.2                                                                         ##STR73##     CH.sub.3                                             ##STR74##                                                                                ##STR75##     "                                                    ##STR76##                                                                                ##STR77##     "                                             14.   CH.sub.2                                                                                  ##STR78##     CH.sub.3                                      15.   "          "              CH.sub.2 CH.sub.3                             16.   "          "              CH.sub.2 CO.sub.2 H                           17.   "          "              CH.sub.2 CONH.sub.2                           18.   "          "                                                                                             ##STR79##                                    19.   "          "              CH.sub.2 SOCH.sub.3                           20.   CH.sub.2 CH.sub.2                                                                        "              CH.sub.3                                      21.   "          "              CH.sub.2 CO.sub.2 H                           22.   "          "              CH.sub.2 CONH.sub.2                           23.   CH.sub.2                                                                                  ##STR80##                                                                                    ##STR81##                                    24.   CH         "              CH.sub.3                                            CH.sub.3                                                                25.   "          "              CH.sub.2 CH.sub.3                             26.   CH.sub.2 CH.sub.2 CH.sub.2                                                               "              CH.sub.3                                      27.   CH.sub.2                                                                                  ##STR82##     CH.sub.3                                      28.   "          "              CH.sub.2 CH.sub.3                             29.   "          "              CH.sub.2 CO.sub.2 H                           30.   "          "              CH.sub.2 CONH.sub.2                           31.   "          "                                                                                             ##STR83##                                    32.   "          "              CH.sub.2 SOCH.sub.3                           33.   CH.sub.2 CH.sub.2                                                                        "              CH.sub.2 CO.sub.2 H                           34.   "          "              CH.sub.2 CONH.sub.2                           35.   "          "                                                                                             ##STR84##                                    36.   CH.sub.2 CH.sub.2                                                                         ##STR85##     CH.sub.2 SOCH.sub.3                           37.   CH         "              CH.sub.3                                            CH.sub.3                                                                38.   CH.sub.2 CH.sub.2 CH.sub.2                                                               "              CH.sub.3                                      39.   CH.sub.2                                                                                  ##STR86##     CH.sub.3                                      40.   CH.sub.2                                                                                  ##STR87##     CH.sub.3                                      41.   "          "              CH.sub.2 CH.sub.3                             42.   CH.sub.2 CH.sub.2                                                                        "              CH.sub.3                                      43.   CH.sub.2                                                                                  ##STR88##     "                                             44.   CH.sub.2 CH.sub.2                                                                        "              "                                             45.   "                                                                                         ##STR89##     "                                             46.   "                                                                                         ##STR90##     "                                             47.   "                                                                                         ##STR91##     "                                             48.   "                                                                                         ##STR92##     "                                             49.   CH.sub.2 CH.sub.2                                                                         ##STR93##     CH.sub.3                                      50.   "                                                                                         ##STR94##     "                                             51.   CH.sub.2 CH.sub.2                                                                         ##STR95##     CH.sub.3                                      52.   "                                                                                         ##STR96##     "                                             53.   "                                                                                         ##STR97##     "                                             54.   "                                                                                         ##STR98##     "                                             55.   "                                                                                         ##STR99##     "                                             56.   "                                                                                         ##STR100##    "                                             57.   CH.sub.2 CH.sub.2                                                                         ##STR101##    CH.sub.3                                      58.   "                                                                                         ##STR102##    "                                             59.   CH.sub.2 CH.sub.2                                                                         ##STR103##    CH.sub.3                                      60.   "                                                                                         ##STR104##    "                                             61.   "                                                                                         ##STR105##    "                                             62.   "                                                                                         ##STR106##    "                                             63.   "                                                                                         ##STR107##    "                                             64.   "                                                                                         ##STR108##    "                                             65.   "                                                                                         ##STR109##    "                                             66.   CH.sub.2 CH.sub.2                                                                         ##STR110##    CH.sub.3                                      67.   "                                                                                         ##STR111##    "                                             68.   "                                                                                         ##STR112##    "                                             69.   "                                                                                         ##STR113##    "                                             70.   "                                                                                         ##STR114##    "                                             71.   "                                                                                         ##STR115##    "                                             72.   "                                                                                         ##STR116##    "                                             73.   CH.sub.2 CH.sub.2                                                                         ##STR117##    CH.sub.3                                      74.   "                                                                                         ##STR118##    "                                             75.   CH.sub.2                                                                                  ##STR119##    CH.sub.3                                      76.   "                                                                                         ##STR120##    "                                             77.   "                                                                                         ##STR121##    "                                             78.   "                                                                                         ##STR122##    "                                             79.   "                                                                                         ##STR123##    "                                             80.   "                                                                                         ##STR124##    "                                             81.   "                                                                                         ##STR125##    "                                             82.   "                                                                                         ##STR126##    "                                             83.   "                                                                                         ##STR127##    "                                             84.   CH.sub.2                                                                                  ##STR128##    CH.sub.3                                      85.   "                                                                                         ##STR129##    "                                             86.   CH.sub.2                                                                                  ##STR130##    CH.sub.3                                      87.   "                                                                                         ##STR131##    "                                             88.   "                                                                                         ##STR132##    "                                             89.   "                                                                                         ##STR133##    "                                             90.   "                                                                                         ##STR134##    "                                             91.   "                                                                                         ##STR135##    "                                             92.   "                                                                                         ##STR136##    "                                             93.   "                                                                                         ##STR137##    "                                             94.   CH.sub.2                                                                                  ##STR138##    CH.sub.3                                      95.   "                                                                                         ##STR139##    "                                             96.   "                                                                                         ##STR140##    "                                             97.   CH.sub.2                                                                                  ##STR141##    CH.sub.3                                      98.   "                                                                                         ##STR142##    "                                             99.   "                                                                                         ##STR143##    "                                             100.  "                                                                                         ##STR144##    "                                             101.  "                                                                                         ##STR145##    "                                             102.  CH.sub.2                                                                                  ##STR146##    CH.sub.3                                      103.  "                                                                                         ##STR147##    "                                             104.  "                                                                                         ##STR148##    CH.sub.2 CN                                   105.  CH.sub.2 CH.sub.2                                                                        "              CH.sub.2 CN                                   106.  CH.sub.3   "              CH.sub.3                                            CHCH.sub.2                                                              107.  "                                                                                         ##STR149##    "                                             108.  CH.sub.2                                                                                  ##STR150##    CH.sub.2 CN                                   109.  CH.sub.2 CH.sub.2                                                                        "              "                                             110.  "                                                                                         ##STR151##    "                                             111.  CH.sub.2   "              "                                             ______________________________________                                    

Internally Alkylated Heteroaryliums--General Procedures ##STR152##

Method I ##STR153##

Method II ##STR154##

Method III ##STR155##

EXAMPLE 4

Preparation of: ##STR156##

A commercial sample of 3M methyl magnesium bromide in ether (0.690 ml,2.07 mmol) is added dropwise to a solution of pyridylthioester 100 (1.0g, 1.4 mmol) in anhydrous tetrahydrofuran (25 ml) at -78° C. under drynitrogen. After 10 min. an additional portion of methyl magnesiumbromide (0.140 ml, 0.42 mmol) is added and stirring is continued for 20min. The reaction mixture is then added to saturated ammonium chloridesolution (35 ml), water (10 ml) and ethyl acetate (40 ml). The phasesare separated and the aqueous layer is extracted with an additionalportion of ethyl acetate (15 ml). The combined organic layers are washedwith cold 1N hydrochloric acid solution, cold 10% aqueous sodiumbicarbonate solution, water and brine. After drying over anhydrousmagnesium sulfate the organic phase is concentrated in vacuo and theresidual gum is chromatographed on silica gel (eluting with 0-10% ethylacetate in methylene chloride) to yield methyl ketone 101.

To a solution of diisopropyl amine (0.120 ml, 0.87 mmol) in anhydroustetrahydrofuran (9 ml) at 0° C. under nitrogen is added 1.3M n-butyllithium in hexane (0.670 ml, 0.87 mmol). After 10 min. at 0° C. thesolution is cooled to -78° C. and a solution of methyl ketone 101 (375mg, 0.58 mmol) in anhydrous tetrahydrofuran (2 ml) is added by syringe.The resulting solution is stirred at -78° C. for 5 min. thenoxodiperoxymolybdenum(pyridine)hexamethylphosphoramide (380 mg, 0.88mmol) is added. The temperature is allowed to rise to -30° C. and thereaction is stirred for 30 min. The reaction is quenched by the additionof saturated sodium sulfite solution (6 ml), 1M potassium dihydrogenphosphate solution (2.4 ml), water (10 ml) and ethyl acetate (25 ml),followed by vigorous stirring for 15 min. After phase separation theaqueous layer is extracted with an additional portion of ethyl acetate(10 ml) and the combined organics are dried over anhydrous magnesiumsulfate. Removal of the solvents in vacuo yields an oil which ischromatographed on silica gel (eluting with ethyl acetate/hexanes) togive hydroxy methyl ketone 102.

A solution of hydroxymethyl ketone 102 (330 mg, 0.50 mmol) indeoxygenated toluene (10 ml) is heated at reflux under an atmosphere ofnitrogen for 1.5 hr., then is cooled and concentrated in vacuo. Theresulting oil is chromatographed on silica gel prep plates (eluting withethyl acetate/hexane) to provide hydroxymethyl carbapenem 103.

A solution of carbapenem 103 (95.3 mg, 0.25 mmol), glacial acetic acid(150 mg, 2.5 mmol), and 1M tetrabutyl ammonium fluoride intetrahydrofuran (1.25 ml, 1.25 mmol) is stirred at ambient temperaturefor 30 hr. under a nitrogen atmosphere. The reaction mixture is thenadded to 0.5M pH 7 phosphate buffer (25 ml), water (25 ml), and ethylacetate (50 ml). The layers are separated and the aqueous layer isextracted with an additional portion of ethyl acetate. The combinedorganic layers are washed with brine and dried over anhydrous magnesiumsulfate. The dried solution is concentrated in vacuo and the residue ischromatographed on silica gel prep plates (eluting with ethylacetate/hexane) to yield dihydroxycarbapenem 104.

A solution of dihydroxycarbapenem 104 (48 mg, 0.18 mmol) and p-toluenesulfonic anhydride (55 mg, 0.18 mmol) in anhydrous methylene chloride (5ml) is cooled to 0° C. and triethylamine (20 mg, 0.20 mmol) is addedslowly by syringe. The resulting solution is stirred at 0° C. for 1 hr,then is diluted with methylene chloride (20 ml) and washed quickly withcold pH 7 phosphate buffer and brine. The organic phase is dried overanhydrous sodium sulfate and the solvent is removed in vacuo to providecrude tosylate 105 which is carried on without further purification.

An ice cold solution of crude tosylate 105 (59 mg, 0.14 mmol) inanhydrous acetonitrile (5 ml) is treated with1-(2-mercaptoethyl)pyridinium nitrate (34 mg, 0.17 mmol) anddiisopropylethylamine (22 mg, 0.17 mmol). The resulting solution isstirred at 0° C. for 10 min., then added to a suspension of celite indiethyl ether (10 ml) and stirred briefly. The celite is filtered offand washed with an additional portion of ether, then is extracted with1:1 tetrahydrofuran/water. The extract is concentrated in vacuo andlyophilized to give pyridinium salt 106. This material is suspended in amixture of methylene chloride (2 ml) and ethyl acetate (2 ml). To thismixture is added a solution of potassium ethylhexanoate in ethyl acetate(0.360 ml of 0.5M solution, 0.18 mmol), triphenyl phosphine (3.3 mg,0.013 mmol) and tetrakis(triphenylphosphine)palladium[0] (0.5 mg, 0.0005mmol). The reaction mixture is stirred under nitrogen at ambienttemperature for 2 hr., then is concentrated in vacuo. The residue ispartitioned between water (5 ml) and ethyl ether (5 ml). The aqueousphase is separated and washed with an additional portion of ether, thenis concentrated in vacuo and chromatographed on two RPS plates (elutingwith ethanol/water). The U.V. active band is removed from the plates andextracted with 4:1 acetonitrile/water. This solution is washed fourtimes with hexanes, then concentrated in vacuo and lyophilized to yieldcompound 107.

EXAMPLE 5

Preparation of: ##STR157##

Triethylamine (56 mg, 0.55 mmol) and methanesulfonyl chloride (63 mg,0.55 mmol) are added to a solution of hydroxymethylketone 102 (330 mg,0.50 mmol) in anhydrous methylene chloride (2 ml) at 0° C. under drynitrogen. After stirring for 30 min. the reaction mixture is added tobrine (10 ml) and methylene chloride (20 ml) containing pH 7 phosphatebuffer (2 ml of 0.5M). After phase separation, the aqueous layer isextracted with an additional portion of methylene chloride and thecombined organics are washed with brine and dried over anhydrousmagnesium sulfate. The dried organic phase is concentrated in vacuo andthe residue is chromatographed on silica gel (eluting with 1:1 ethylacetate/hexane) to provide mesylate 108.

Triethylamine (40 mg, 0.40 mmol) and 3-thiomethylpyridine (50 mg, 0.40mmol) are added at 0° C. to a solution of mesylate 108 (280 mg, 0.38mmol) in dry dimethylformamide (5 ml). The reaction mixture is allowedto warm to ambient temperature where it is aged for 2.5 hr. The reactionis then diluted with 1M dipotassium hydrogen phosphate (5 ml), brine (5ml) and ethyl acetate (20 ml) and the layers are separated. The aqueouslayer is extracted with an additional portion of ethyl acetate (8 ml)and the combined organics are washed with brine and dried over anhydrousmagnesium sulfate. Removal of solvents in vacuo gives a gum which ischromatographed on silica gel (eluting with 1:1 ethyl acetate/hexane) toyield ketone 109.

Ketone 109 (192 mg, 0.25 mmol) is stirred under nitrogen at ambienttemperature in a solution of 0.2M hydrochloric acid in 9:1methanol/water (5 ml) for 6 hr. The reaction mixture is then added to 1Mdipotassium hydrogen phosphate (5 ml), 1M potassium dihydrogen phosphate(5 ml), water and ethyl acetate (15 ml). After separation of the layers,the aqueous layer is extracted with an additional portion of ethylacetate and the combined organics are washed with brine and dried overanhydrous magnesium sulfate. Solvents are removed in vacuo to yield aresidue which is chromatographed on silica gel (eluting with ethylacetate/methylene chloride) to yield carbinol 110.

A solution of ketocarbinol 110 (111 mg, 0.17 mmol) in deoxygenatedtoluene (4 ml) is heated at reflux under dry nitrogen for 6 hr., thenconcentrated in vacuo to give an oil. This material was chromatographedon silica gel preparative plates (eluting with ethyl acetate/methylenechloride) to provide carbapenem 111.

A solution of carbapenem 111 (41 mg, 0.11 mmol) in dry methylenechloride (4 ml) is cooled in an ice-water bath prior to the addition ofmethyl fluorosulfonate (14 mg, 0.12 mmol). The reaction mixture isstirred at 0° C. for 1 hr. during which time an oily precipitate forms.The methylene chloride is removed by decantation and the residue iswashed with methylene chloride, subjected to high vacuum, thentriturated with i-propanol and filtered. The resulting solid is added tomethylene chloride (2 ml) and ethyl acetate (2 ml). To this mixture isadded a solution of potassium ethyl hexanoate in ethyl acetate (0.22 mlof 0.5M, 0.11 mmol), tetrakis(triphenylphosphine)palladium (0.4 mg,0.0003 mmol), and triphenyl phosphine (2 mg, 0.008 mmol). The resultingmixture is stirred at ambient temperature for 2.5 hr., then isconcentrated in vacuo. The residue is partitioned between water andethyl acetate. The aqueous layer is washed with an additional portion ofethyl acetate, then is concentrated and charged onto a column of Dowex50W-X4 resin (sodium form, 200-400 mesh) which is eluted with water.Fractions containing the desired pyridinium product are pooled,concentrated, and lyophilized to provide product 112.

EXAMPLE 6 ##STR158##

An ice cold solution of tosylate 105 (84 mg, 0.20 mmol) in anhydrousacetonitrile (5 ml) is treated with a solution ofN-methyl-N'-mercaptomethylimidazolium perchlorate (48 mg, 0.21 mmol) inacetonitrile (0.25 ml) and with diisopropylethylamine (32 mg, 0.25mmol). The mixture is stirred at 0° C. for 15 min., then is added to asuspension of celite in diethyl ether (10 ml) and stirred for 3 min. Thecelite is filtered off, washed with an additional portion of ether andextracted with 1:1 tetrahydrofuran/water. The extract is concentrated invacuo lyophilized to give crude 113. This material is suspended in amixture of methylene chloride (2 ml) and ethyl acetate (2 ml). To thismixture is added a solution of potassium ethylhexanoate in ethyl acetate(0.40 ml of 0.5M solution, 0.20 mmol), triphenylphosphine (3.4 mg, 0.014mmol) and tetrakis(triphenylphosphine)palladium[0] (0.5 mg, 0.0005mmol). The reaction mixture is stirred under nitrogen at ambienttemperature for 2 hr., then is concentrated in vacuo. The residue ispartitioned between water (5 ml) and ethyl ether (5 ml). The aqueousphase is separated and washed with an additional portion of ether, thenis concentrated in vacuo and chromatographed on two RPS plates (elutingwith ethanol/water). The U.V. active band is removed from the plates andextracted with 4:1 acetonitrile/water. This solution is washed fourtimes with hexanes, then concentrated in vacuo and lyophilized to yieldcompound 114.

EXAMPLE 7

Preparation of: ##STR159##

To a solution of diisopropylamine (159 mg, 1.6 mmol) in anhydroustetrahydrofuran (15 ml) at 0° C. under dry nitrogen is added 2.2Mn-butyllithium in hexane (0.727 ml, 1.6 mmol). After 10 min. thesolution is cooled to -78° C. and a solution of methyl ketone 101 (965mg, 1.5 mmol) in anhydrous tetrahydrofuran (2 ml) is added by syringe.The resulting solution is stirred at -78° C. for 10 min. then a solutionof thiolsulfonate 115 (424 mg, 1.6 mmol) in anhydrous tetrahydrofuran (1ml) is added by syringe. After an additional 30 min. the reaction isquenched by the addition of saturated aqueous ammonium chloride solution(5 ml) and the resulting mixture is poured into water (20 ml) and ethylacetate (35 ml). The layers are separated and the aqueous layer isextracted with an additional portion of ethyl acetate (10 ml). Thecombined organics are dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resulting residue is chromatographed onsilica gel (eluting with ethyl acetate/hexanes) to yield compound 116.

Ketone 116 (843 mg, 1.1 mmol) is stirred at ambient temperature in asolution of 0.2N hydrochloric acid in 9:1 methanol/water (16 ml) for 8hr. The reaction mixture is then added to 1M dipotassium hydrogenphosphate (20 ml), 1M potassium dihydrogen phosphate (20 ml), water andethyl acetate (50 ml). The layers are separated and the aqueous layer isextracted with an additional portion of ethyl acetate (15 ml). Thecombined organic layers are washed with brine, dried over magnesiumsulfate and concentrated in vacuo to yield an oil. This material ischromatographed on silica gel (eluting with ethyl acetate/hexanes) toprovide hydroxyketone 117.

A solution of hydroxyketone 117 (424 mg, 0.65 mmol) in deoxygenatedxylene (13 ml) containing a trace of hydroquinone is heated at 130°under dry nitrogen for 7.5 hr. The reaction mixture is then cooled,concentrated in vacuo and the residue is chromatographed on silica gel(eluting with ethyl acetate/methylene chloride) to yield carbapenem 118.

A solution of carbapenem 118 (50 mg, 0.13 mmol) in dry methylenechloride (5 ml) is cooled in an ice-water bath prior to the addition ofmethyl fluorosulfonate (16 mg, 0.14 mmol). The reaction mixture isstirred at 0° C. for 1 hr. during which time an oily precipitate forms.The methylene chloride is removed by decantation and the residue iswashed with methylene chloride, subjected to high vacuum, thentriturated with i-propanol and filtered. The resulting solid whichcontains compound 119, is added to methylene chloride (2 ml) and ethylacetate (2 ml). To this mixture is added a solution of potassium ethylhexanoate in ethyl acetate (0.26 ml of 0.5M, 0.13 mmol),tetrakis(triphenylphosphine)palladium (0.4 mg, 0.0003 mmol), andtriphenyl phosphine (2.4 mg, 0.009 mmol). The resulting mixture isstirred at ambient temperature for 2.5 hr., then is concentrated invacuo. The residue is partitioned between water and ethyl acetate. Theaqueous layer is washed with an additional portion of ethyl acetate,then is concentrated and charged onto a column of Dowex 50W-X4 resin(sodium form, 200-400 mesh) which is eluted with water. Fractionscontaining the desired pyridinium product are pooled, concentrated, andlyophilized to provide product 120.

EXAMPLE 8

Utilizing the procedures of Examples 4-7, the following internallyalkylated compounds listed in Table II are prepared:

                  TABLE II                                                        ______________________________________                                         ##STR160##                                                                    ##STR161##                                                                    B                                                                                         ##STR162##                                                       ______________________________________                                        CH.sub.2 CH.sub.2                                                                          ##STR163##                                                       CH.sub.2 CH.sub.2                                                                          ##STR164##                                                       CH.sub.2 CH.sub.2                                                                          ##STR165##                                                       CH.sub.2 CH.sub.2                                                                          ##STR166##                                                       CH.sub.2 CH.sub.2                                                                          ##STR167##                                                       CH.sub.2 CH.sub.2                                                                          ##STR168##                                                       CH.sub.2 CH.sub.2                                                                          ##STR169##                                                       CH.sub.2 CH.sub.2                                                                          ##STR170##                                                       CH.sub.2 CH.sub.2                                                                          ##STR171##                                                       CH.sub.2 CH.sub.2                                                                          ##STR172##                                                       CH.sub.2 CH.sub.2                                                                          ##STR173##                                                       CH.sub.2 CH.sub.2                                                                          ##STR174##                                                       CH.sub.2 CH.sub.2                                                                          ##STR175##                                                       CH.sub.2 CH.sub.2                                                                          ##STR176##                                                       CH.sub.2 CH.sub.2                                                                          ##STR177##                                                       CH.sub.2 CH.sub.2                                                                          ##STR178##                                                       CH.sub.2 CH.sub.2                                                                          ##STR179##                                                       CH.sub.2 CH.sub.2                                                                          ##STR180##                                                       CH.sub.2 CH.sub.2                                                                          ##STR181##                                                       CH.sub.2 CH.sub.2                                                                          ##STR182##                                                       CH.sub.2 CH.sub.2                                                                          ##STR183##                                                       CH.sub.2 CH.sub.2                                                                          ##STR184##                                                       CH.sub.2 CH.sub.2                                                                          ##STR185##                                                       CH.sub.2 CH.sub.2                                                                          ##STR186##                                                       CH.sub.2 CH.sub.2                                                                          ##STR187##                                                       CH.sub.2 CH.sub.2                                                                          ##STR188##                                                       CH.sub.2 CH.sub.2                                                                          ##STR189##                                                       CH.sub.2 CH.sub.2                                                                          ##STR190##                                                       CH.sub.2 CH.sub.2                                                                          ##STR191##                                                       CH.sub.2 CH.sub.2                                                                          ##STR192##                                                       CH.sub.2 CH.sub.2                                                                          ##STR193##                                                       CH.sub.2 CH.sub.2                                                                          ##STR194##                                                       CH.sub.2 CH.sub.2                                                                          ##STR195##                                                       CH.sub.2 CH.sub.2                                                                          ##STR196##                                                       CH.sub.2 CH.sub.2                                                                          ##STR197##                                                       CH.sub.2 CH.sub.2                                                                          ##STR198##                                                       CH.sub.2 CH.sub.2                                                                          ##STR199##                                                       CH.sub.2 CH.sub.2                                                                          ##STR200##                                                       CH.sub. 2 CH.sub.2                                                                         ##STR201##                                                       CH.sub.2 CH.sub.2                                                                          ##STR202##                                                       CH.sub.2 CH.sub.2                                                                          ##STR203##                                                       CH.sub.2 CH.sub.2                                                                          ##STR204##                                                       CH.sub.2 CH.sub.2                                                                          ##STR205##                                                       CH.sub.2 CH.sub.2                                                                          ##STR206##                                                       CH.sub.2 CH.sub.2                                                                          ##STR207##                                                       CH.sub.2 CH.sub.2                                                                          ##STR208##                                                       CH.sub.2 CH.sub.2                                                                          ##STR209##                                                       CH.sub.2 CH.sub.2                                                                          ##STR210##                                                       CH.sub.2 CH.sub.2                                                                          ##STR211##                                                       CH.sub.2 CH.sub.2                                                                          ##STR212##                                                       CH.sub.2 CH.sub.2                                                                          ##STR213##                                                       CH.sub.2 CH.sub.2                                                                          ##STR214##                                                       CH.sub.2 CH.sub.2                                                                          ##STR215##                                                       CH.sub.2 CH.sub.2                                                                          ##STR216##                                                       CH.sub.2 CH.sub.2                                                                          ##STR217##                                                       CH.sub.2 CH.sub.2                                                                          ##STR218##                                                       CH.sub.2 CH.sub.2                                                                          ##STR219##                                                       CH.sub.2 CH.sub.2                                                                          ##STR220##                                                       CH.sub.2 CH.sub.2                                                                          ##STR221##                                                       CH.sub.2 CH.sub.2                                                                          ##STR222##                                                       CH.sub.2 CH.sub.2                                                                          ##STR223##                                                       CH.sub.2 CH.sub.2                                                                          ##STR224##                                                       CH.sub.2 CH.sub.2                                                                          ##STR225##                                                       CH.sub.2 CH.sub.2                                                                          ##STR226##                                                       CH.sub.2 CH.sub.2                                                                          ##STR227##                                                       CH.sub.2 CH.sub.2                                                                          ##STR228##                                                       CH.sub.2 CH.sub.2                                                                          ##STR229##                                                       CH.sub.2 CH.sub.2                                                                          ##STR230##                                                       CH.sub.2 CH.sub.2                                                                          ##STR231##                                                       CH.sub.2 CH.sub.2                                                                          ##STR232##                                                       CH.sub.2 CH.sub.2                                                                          ##STR233##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR234##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR235##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR236##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR237##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR238##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR239##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR240##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR241##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR242##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR243##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR244##                                                       CH.sub.2                                                                                   ##STR245##                                                       CH.sub.2                                                                                   ##STR246##                                                       CH.sub.2                                                                                   ##STR247##                                                       CH(CH.sub.3)                                                                               ##STR248##                                                       CH.sub.2 CH.sub.2 CH.sub.2                                                                 ##STR249##                                                       CH.sub.2 CH.sub.2                                                                          ##STR250##                                                       CH.sub.2 CH.sub.2                                                                          ##STR251##                                                       CH.sub.2 CH.sub.2                                                                          ##STR252##                                                       CH.sub.2                                                                                   ##STR253##                                                       CH.sub.2                                                                                   ##STR254##                                                       CH.sub.2                                                                                   ##STR255##                                                       CH.sub.2                                                                                   ##STR256##                                                       CH.sub.2                                                                                   ##STR257##                                                       CH.sub.2                                                                                   ##STR258##                                                        CH.sub.2                                                                                  ##STR259##                                                       CH.sub.2                                                                                   ##STR260##                                                       CH.sub.2                                                                                   ##STR261##                                                       CH.sub.2                                                                                   ##STR262##                                                       CH.sub.2                                                                                   ##STR263##                                                       CH.sub.2                                                                                   ##STR264##                                                       CH.sub.2                                                                                   ##STR265##                                                       CH.sub.2                                                                                   ##STR266##                                                       CH.sub.2                                                                                   ##STR267##                                                       CH.sub.2 CH.sub.2                                                                          ##STR268##                                                       CH.sub.2 CH.sub.2                                                                          ##STR269##                                                       CH.sub.2 CH.sub.2                                                                          ##STR270##                                                       CH.sub.2 CH.sub.2                                                                          ##STR271##                                                       CH.sub.2 CH.sub.2                                                                          ##STR272##                                                       CH.sub.2 CH.sub.2                                                                          ##STR273##                                                       CH.sub.2 CH.sub.2                                                                          ##STR274##                                                       CH.sub.2 CH.sub.2                                                                          ##STR275##                                                       CH.sub.2 CH.sub.2                                                                          ##STR276##                                                       CH.sub.2 CH.sub.2                                                                          ##STR277##                                                       CH.sub.2 CH.sub.2                                                                          ##STR278##                                                       CH.sub.2 CH.sub.2                                                                          ##STR279##                                                        CH.sub.2 CH.sub.2                                                                         ##STR280##                                                       CH.sub.2 CH.sub.2                                                                          ##STR281##                                                       CH.sub.2 CH.sub.2                                                                          ##STR282##                                                       CH.sub.2 CH.sub.2                                                                          ##STR283##                                                       CH.sub.2 CH.sub.2                                                                          ##STR284##                                                       CH.sub.2 CH.sub.2                                                                          ##STR285##                                                       CH.sub.2 CH.sub.2                                                                          ##STR286##                                                       CH.sub.2 CH.sub.2                                                                          ##STR287##                                                       CH.sub.2 CH.sub.2                                                                          ##STR288##                                                       CH.sub.2 CH.sub.2                                                                          ##STR289##                                                       CH.sub.2 CH.sub.2                                                                          ##STR290##                                                       CH.sub.2 CH.sub.2                                                                          ##STR291##                                                       CH.sub.2 CH.sub.2                                                                          ##STR292##                                                       CH.sub.2 CH.sub. 2                                                                         ##STR293##                                                       CH.sub.2 CH.sub.2                                                                          ##STR294##                                                       CH.sub.2 CH.sub.2                                                                          ##STR295##                                                       CH.sub.2 CH.sub.2                                                                          ##STR296##                                                       CH.sub.2 CH.sub.2                                                                          ##STR297##                                                       CH.sub.2 CH.sub.2                                                                          ##STR298##                                                       CH.sub.2 CH.sub.2                                                                          ##STR299##                                                       CH.sub.2 CH.sub.2                                                                          ##STR300##                                                       CH.sub.2 CH.sub.2                                                                          ##STR301##                                                       CH.sub.2 CH.sub.2                                                                          ##STR302##                                                       CH.sub.2 CH.sub.2                                                                          ##STR303##                                                       CH.sub.2 CH.sub.2                                                                          ##STR304##                                                       CH.sub.2 CH.sub.2                                                                          ##STR305##                                                       CH.sub.2 CH.sub.2                                                                          ##STR306##                                                       CH.sub.2 CH.sub.2                                                                          ##STR307##                                                        ##STR308##                                                                                ##STR309##                                                       CH.sub.2                                                                                   ##STR310##                                                       CH.sub.2                                                                                   ##STR311##                                                       CH.sub.2                                                                                   ##STR312##                                                       CH.sub.2                                                                                   ##STR313##                                                       CH.sub.2                                                                                   ##STR314##                                                       CH.sub.2                                                                                   ##STR315##                                                       CH.sub.2                                                                                   ##STR316##                                                       CH.sub.2                                                                                   ##STR317##                                                       CH.sub.2                                                                                   ##STR318##                                                       CH.sub.2                                                                                   ##STR319##                                                       CH.sub.2                                                                                   ##STR320##                                                       CH.sub.2                                                                                   ##STR321##                                                       CH.sub.2                                                                                   ##STR322##                                                       CH.sub.2 CH.sub.2                                                                          ##STR323##                                                       CH.sub.2 CH.sub.2                                                                          ##STR324##                                                       CH.sub.2 CH.sub.2                                                                          ##STR325##                                                       CH.sub.2 CH.sub.2                                                                          ##STR326##                                                       CH.sub.2 CH.sub.2                                                                          ##STR327##                                                       CH.sub.2 CH.sub.2                                                                          ##STR328##                                                       CH.sub.2 CH.sub.2                                                                          ##STR329##                                                       CH.sub.2 CH.sub.2                                                                          ##STR330##                                                       CH.sub.2 CH.sub.2                                                                          ##STR331##                                                       CH.sub.2 CH.sub.2                                                                          ##STR332##                                                       CH.sub.2 CH.sub.2                                                                          ##STR333##                                                       CH.sub.2 CH.sub.2                                                                          ##STR334##                                                       CH.sub.2 CH.sub.2                                                                          ##STR335##                                                       CH.sub.2 CH.sub.2                                                                          ##STR336##                                                       CH.sub.2 CH.sub.2                                                                          ##STR337##                                                       CH.sub.2 CH.sub.2                                                                          ##STR338##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR339##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR340##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR341##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR342##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR343##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR344##                                                       CH(CH.sub.3)CH.sub.2                                                                       ##STR345##                                                       ______________________________________                                    

What is claimed is:
 1. A compound having the formula: ##STR346##wherein: R¹ is hydrogen,R⁴ and R⁵ are independently H, CH₃ --, CH₃ CH₂--, (CH₃)₂ CH--, HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂, F₂ CH--,F₃ C--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--; X is --S--, --SO--,--SO₂ --, --O-- or --NH--; L is a bridging group comprising substitutedor unsubstituted C₁ -C₄ straight, C₂ -C₆ branched or C₃ -C₇ cycloalkylgroups wherein the substituents are selected from C₁ -C₆ alkyl, O--C₁-C₆ alkyl, S--C₁ -C₆ alkyl, CF₃, N(C₁ -C₆ alkyl)₂ ; Het is a mono- orbicyclic heteroarylium group containing from 5-11 ring atoms of which upto 5 are heteroatoms, in addition to the quaternary nitrogen, being ofthe formula: ##STR347## wherein: R² is(1) an unsubstituted orsubstituted C₁ -C₆ alkyl radical; (2) an unsubstituted or substituted C₂-C₆ alkenyl radical; (3) an unsubstituted or substituted C₂ -C₆ alkynylradical; (4) a C₃ -C₇ cycloalkyl radical in which the ring issubstituted or unsubstituted and one or more atoms may be replaced by aheteroatom; (5) a C₃ -C₇ cycloalkyl methyl radical in which the ring maybe substituted and one or more atoms may be replaced by a heteroatom;(6) an unsubstituted or substituted C₅ -C₇ cycloalkenyl radical; (7) anunsubstituted or substituted bivalent C₂ -C₆ alkyidene radical,optionally interrupted by a heteroatom, and joined to the heteroaryliumgroup to form a ring which is carbocyclic or in which one or more atomsis replaced by a heteroatom and wherein the new ring may contain one ormore double bonds; (8) an unsubstituted or substituted phenyl orheteroaryl radical; (9) an unsubstituted or substituted phenyl (C₁ -C₄alkyl) or heteroaryl (C₁ -C₄ alkyl) radical; (10) a cyano (C₁ -C₄ alkyl)radical; (11) a carboxy (C₁ -C₄ alkyl) radical; (12) a sulfo (C₁ -C₄alkyl) radical; (13) a carbamoyl (C₁ -C₄ alkyl) radical; (14) aphosphonyl (C₁ -C₄ alkyl) radical; (15 ) a hydroxy (C₁ -C₄ alkyl)radical; or (16) an amino (C₁ -C₄ alkyl) radical in which the nitrogenatom is unsubstituted or substituted with one to three C₁ -C₄ alkylgroups;wherein the substituents in the above definitions of R² areindependently selected from the group consisting of: (a) atrifluoromethyl group; (b) a halogen atom; (c) an unsubstituted orsubstituted C₁ -C₄ alkoxyl radical; (d) a hydroxy group; (e) anunsubstituted or substituted (C₁ -C₆ alkyl) carbonyloxy radical; (f) acarbamoyloxy radical which is unsubstituted or substituted on nitrogenwith one or two C₁ -C₄ alkyl groups; (g) a C₁ -C₆ alkylthio radical, C₁-C₆ alkylsulfinyl radical or C₁ -C₆ alkylsulfonyl radical, each of whichis unsubstituted or substituted on the alkyl group; (h) a sulfo group;(i) a sulfamoyl group which is unsubstituted or substituted on nitrogenby one or two C₁ -C₄ alkyl groups; (ia) an amino group; (ib) a mono (C₁-C₄ alkyl) amino or di(C₁ -C₄ alkyl)amino group, each of which isunsubstituted or unsubstituted on the alkyl group; (j) a formylaminogroup; (k) an unsubstituted or substituted (C₁ -C₆ alkyl)carbonylaminoradical; (1) a (C₁ -C₄ alkoxyl) carbonylamino radical; (m) a ureidogroup in which the terminal nitrogen is unsubstituted or substitutedwith one or two C₁ -C₄ alkyl groups; (n) an arylsulfonamido or a (C₁ -C₆alkyl) sulfonamido group; (o) a cyano group; (p) a formyl or acetalizedformyl radical; (q) an unsubstituted or substituted (C₁ -C₆alkyl)carbonyl radical wherein the carbonyl is free or acetalized; (r)an unsubstituted or substituted phenylcarbonyl or heteroarylcarbonylradical; (ra) a hydroximinomethyl radical in which the oxygen or carbonatom is optionally substituted by a C₁ -C₄ alkyl group; (s) a carboxylgroup; (t) a (C₁ -C₆ alkoxy)carbonyl radical; (u) a carbamoyl radicalwhich is unsubstituted or substituted on nitrogen by one or two C₁ -C₄alkyl groups; (v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoylradical in which the nitrogen atom may be additionally substituted by aC₁ -C₄ alkyl group; (w) a thiocarbamoyl group; (x) a 5-(1H)-tetrazolylgroup; (xa) an amidino group ##STR348## where R', R" and R'" areindependently hydrogen, C₁ -C₄ alkyl or wherein two of the alkyl groupstogether form a C₂ -C₆ alkylidene radical optionally interrupted by aheteroatom and joined together to form a ring; (xb) a carboxamidinogroup ##STR349## where R', R" and R'" are defined above; (xc) aguanidinyl group where R" in (ab) above is NR^(iv) R^(v) and R^(iv) andR^(v) are as defined for R' through R'" above; (y) a phosphonate group--P(O)(OH)OR' where R' is C₁ -C₃ alkyl; (z) an alkyl phosphonate group--(CH₂)_(n) P(O)(0H)(OR') where n=1 to 3 and R' is C₁ -C₃ alkyl; (aa)hydrogen; (ab) an unsubstituted or substituted C₁ -C₆ alkyl radical;(ac) an unsubstituted or substituted C₂ -C₆ alkenyl radical; (ad) anunsubstituted or substituted C₂ -C₆ alkynyl radical; (ae) a C₃ -C₇cycloalkyl radical in which the ring is substituted or unsubstituted andone or more atoms may be replaced by a heteroatom; (af) a C₃ -C₇cycloalkyl methyl radical in which the ring may be substituted and oneor more atoms may be replaced by a heteroatom; (ag) an unsubstituted orsubstituted C₅ -C₇ cycloalkenyl radical; (ah) an unsubstituted orsubstituted phenyl or heteroaryl radical; and (ai) an unsubstituted orsubstituted phenyl (C₁ -C₄ alkyl) or heteroaryl (C₁ -C₄ alkyl) radical;and (a) hydrogen; (b) an unsubstituted or substituted C₁ -C₆ alkylradical; (c) an unsubstituted or substituted C₂ -C₆ alkenyl radical; (d)an unsubstituted or substituted C₂ -C₆ alkynyl radical; (e) a C₃ -C₇cycloalkyl radical in which the ring is substituted or unsubstituted andone or more atoms may be replaced by a heteroatom; (f) a C₃ -C₇cycloalkyl methyl radical in which the ring may be substituted and oneor more atoms may be replaced by a heteroatom; (g) an unsubstituted orsubstituted C₅ -C₇ cycloalkenyl radical; (h) an unsubstituted orsubstituted phenyl or heteroaryl radical; (i) an unsubstituted orsubstituted phenyl (C₁ -C₄ alkyl) or heteroaryl (C₁ -C₄ alkyl) radical;and (j) a trifluoromethyl group; (k) a halogen atom; (l) anunsubstituted or substituted C₁ -C₄ alkoxyl radical; (m) a C₁ -C₆alkylthio radical, C₁ -C₆ alkylsulfinyl radical or C₁ -C₆ alkylsulfonylradical, each of which is unsubstituted or substituted on the alkylgroup; (n) a mono (C₁ -C₄ alkyl) amino or di(C₁ -C₄ alkyl)amino group,each of which is unsubstituted or substituted on the alkyl group; or (o)a cyano group; and (i) COOH or a pharmaceutically acceptable ester orsalt thereof, (ii) COOR wherein R is a removable carboxy protectinggroup, (iii) COOM wherein M is an alkali metal, or (iv) COO⁻ ; providedthat when Y is other than (iv) a counterion Z⁻ is provided.
 2. Acompound of claim 1 wherein R¹ is hydrogen.
 3. A compound of claim 1wherein L is substituted or unsubstituted branched or linear C₁ -C₄alkyl.
 4. A compound of claim 3 wherein L is --CH₂ --, --CH(CH₃)--,--(CH₂)₂ --, or --CH(CH₃)CH₂ --.
 5. A compound of claim 1 wherein Het ismonocyclic heteroarylium having 5-6 ring atoms.
 6. A compound of claim 5wherein Het is a pyridinium, diazolium, triazolium, thiazolium oroxazolium group.
 7. A compound of claim 1 wherein R² is an unsubstitutedor substituted C₁ -C₆ alkyl group, carboxy (C₁ -C₄ alkyl), carbamoyl (C₁-C₄ alkyl), sulfo (C₁ -C₄ alkyl), heteroaryl (C₁ -C₄ alkyl), or cyano(C₁ -C₄ alkyl).
 8. A compound of claim 1 wherein R³ is hydrogen, N(C₁-C₃ alkyl), O--C₁ -C₄ alkyl, C₁ -C₄ alkyl, CN, CF₃ or CH₂ OH.
 9. Acompound of claim 1 wherein the compound is a member selected from thegroup wherein R¹ is H and ##STR350## is selected from ##STR351##
 10. Acompound of claim 1 wherein ##STR352## is monocyclic.
 11. The compoundof claim 10 wherein L is unsubstituted or substituted C₁ -C₆ alkylwherein the substituents are NH₂, CF₃, OH or C₁ -C₄ alkoxy, CN, orCONH₂.
 12. The compound of claim 10 wherein the --N⁺ group is asubstituted or unsubstituted pyridinium, pyridazinium, pyrimidinium,pyrazinium, pyrazolium, imidazolium or triazolium.
 13. The compound ofclaim 12 wherein the --N³⁰ group is substituted or unsubstitutedpyridinium or pyrazinium, wherein the substituent is NH₂, OH,CH═N--OCH₃, C₁ -C₃ alkyl, CF₃, CONH₂, COOH, halo, C₁ -C₃ alkoxy, SO₃ H,CHO, CN, ##STR353## N(C₁ -C₃ alkyl)₂, NH(C₁ -C₃ alkyl), CH₂ CO₂ H, CH₂SO₃ H, CH₂ OH, CH₂ CN, CH₂ CONH₂, or CH₂ N(C₁ -C₃ alkyl)₂.
 14. Thecompound of claim 11 wherein L is --CH₂ --, --CH₂ --CH₂ -- or ##STR354##15. The compound of claim 14 wherein ##STR355## is substituted orunsubstituted pyridinium.
 16. The compound of claim 15 wherein said##STR356## group is pyridinium, carboxypyridinium, hydroxypyridinium, C₁-C₃ alkylpyridinium or diC₁ -C₃ alkylaminopyridinium.
 17. The compoundof claim 16 wherein L is --(CH₂)₂ -- or --CH(CH₃)--CH₂ --.
 18. Thecompound of claim 17 wherein Y is (iv) and ##STR357##
 19. The compoundof claim 18 wherein ##STR358##
 20. The compound of claim 17 wherein Y is(iii) and ##STR359##
 21. The compound of claim 20 wherein ##STR360## 22.A compound of claim 1 having the sterochemical configuration: ##STR361##23. The combination of a compound of claim 1 and a DHP inhibitor. 24.The combination of claim 13 wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoicacid.
 25. A pharmaceutical composition for antibiotic use comprising anantibacterially effective amount of a compound of claim 1, aninhibitorily effective amount of a DHP inhibitor, and, optionally, apharmaceutically acceptable carrier.
 26. A pharmaceutical compositionaccording to claim 14 wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxyamido)-2-heptenoicacid.
 27. A method of treating bacterial infections in human or animalsubjects in need of such treatment comprising coadministering to saidsubjects an antibacterially effective amount of a compound of claim 1,an inhibitorily effective amount of a DHP inhibitor.
 28. A methodaccording to claim 27 wherein the DHP inhibitor is7-(L-2-amino2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoicacid.
 29. A pharmaceutical composition for antibiotic use comprising anantibacterially effective amount of a compound of claim 1, and,optionally, a pharmaceutically acceptable carrier.
 30. A method oftreating bacterial infections in human or animal subjects in need ofsuch treatment comprising administering to said subjects anantibacterially effective amount of a compound of claim 1.